DCS and the immune system redux

[Kevrumbo]

<Dr Deco>
Exercise is a big player, and I have mentioned it many times over the ten years of existence of &#8220;Ask Dr Deco.&#8221; [In addition, it is in the scientific literature.] Nevertheless, the vast majority of the postings have responders asking &#8220;Were you hydrated?&#8221; This is something that has been shown to not be of importance except in extreme cases. No one asks about exercise, &#8220;Did you push, pull, or strain?&#8221;

Yes . . .in my type I DCS incident (joint pain left shoulder & upper arm), I suffered a painful musculoskeletal strain of the left shoulder while manipulating stage bottles at depth, before ascending on a non-optimal decompression profile. (My dive buddy on the same flawed profile, on-the-other-hand, did not exhibit any signs/symptoms of DCS post-dive). So you see Dr. Deco, based on my anecdotal experience as a patient, I'm very much interested in the Immuno/Inflammatory pathophysiological response as related or contributory to DCS. . .

http://www.scubaboard.com/forums/5284043-post29.html

 

[ScubaFeenD]

I am interested in the Immune mediated DCS profile hypothesis. I feel like some immune component would play a role, but im not sure to what extent complement would play with bubble formation when Ig levels are low and not fixed to antigen. This is, of course, presuming that Antibodies arent somehow binding/aggregating on microbubbles. However, I feel like this hypothesis could be tested clinically with the use of anti-inflammatory drug administration to patients experiencing DCS symptoms (in conjunction with re compression therapy since it is the gold standard currently). Presumably, if immune mediated reactions were going on, drugs to minimize an immune response should be able to help. However, the unfortunate down side of this would be that an exact mechanism of immune mediation could not be determined as anti-inflammatory drugs tend to have more broadly acting side effects on blood. Nevertheless it would be interesting to see what happens in patients and if potential long term side effects could be reduced.

I mean hell, any hypothesis is worth testing, right?

 

[Kevrumbo]

There was an article about deep cave diver Ann Kristovich DDS, proposing that corticosteroid injections for treatment of type I DCS (and type II??) could be useful in remote locations, in lieu of immediate access/transport to a hyperbaric chamber.

Also, some old background info:

Some physicians also recommend corticosteroids in DCS to decrease inflammation,
but their use is largely anecdotal and efficacy is unproven (Catron 1982). Various
other drugs, such as heparin, diazepam, aspirin, and vasodilators, have been studied
or used in this condition (Catron 1982); none can be routinely recommended as
effective. Except for oxygen, which can be considered a drug, no particular drug is
helpful for DCS. (p.142, http://www.craigmossonline.net/option2/scubaexpl.pdf)

Catron PW, Flynn ET. Adjuvant drug therapy for decompression sickness: a review. Undersea Biomed Res 1982;9:161&#8211;173.

 

[DocVikingo]

A recent animal study seems to show no real promise for the anti-inflammatory drug methylprednisolone (MP).

Here's the reference followed by 2 excerpts:

"Aviation, Space, and Environmental Medicine; Vol. 79, No. 1, January , 2008, Page 7 -13.

Pharmacological Interventions to Decompression Sickness in Rats: Comparison of Five Agents

Elizabeth A. Montcalm-Smith, Andreas Fahlman and Susan R. Kayar

From the Naval Medical Research Center, Silver Spring, MD (E. A. Montcalm-Smith, S. R. Kayar), and the UBC Marine Mammal Research Unit, The University of British Columbia, Vancouver, BC, Canada (A. Fahlman).

"Agents

Methylprednisolone (MP)

An anti-inflammatory steroid, MP has been suggested as a DCS therapy because it may reduce cerebral edema caused by gas emboli (5). MP may also improve blood flow to brain regions injured by gas emboli by reducing the adherence of leukocytes to damaged vascular endothelium (17). In swine subjected to a 24-h saturation dive, MP administered 24 h prior to decompression did not protect against DCS; in fact, it increased the death rate of animals with DCS (15). However, after 24 h, the MP was probably no longer at its peak activity. Consideration of corticosteroids as emergency therapy for DCS persists (10) based on their anti-inflammatory action (5,42) and because some trials showed long-term benefits from MP in patients suffering from spinal cord trauma (6). Treatment of DCS with another glucocorticoid, Dexamethasone, did not appear to influence the outcome of DCS (20). We used a rat model of DCS to test the predive administration of MP using our dive protocol that favors neurological symptoms of DCS."

"Results: Our results show that MP might offer benefit as an adjuvant treatment for DCS in a rat model. MP caused a statistically significant delay in the onset of DCS (Fig. 2), but DCS incidence was the same in treated and control animals. Although high-dose MP is commonly administered after spinal cord injury, this is not the case with DCS. While MP has never been tested in humans for DCS, animal studies show that it did not protect against severe DCS; in fact, treated animals with DCS had higher mortality (14). In addition, there are potentially serious adverse reactions to the use of parenteral corticosteroids, such as gastrointestinal bleeding and pancreatitis. Mega-dose MP has been associated with anaphylaxis, hyperglycemia, infection, bradycardia, exacerbation of hypertension, seizure, and sudden death (21)."

Regards,

DocVikingo

 

[Kevrumbo]

.....

. . .Long thought to be a simple process of blockage of vessels and infarction, it has now been shown that there is a tripping of the complement system and the immune system (T- and B- leucocytes) when bubbles form from decompression. This immune response has a domino effect on blood chemistry that leads to marked changes in the tissues long after the bubbles are gone.

Work has also been done that shows the importance of early treatment. The longer the period of waiting after a decompression incident, the more blood chemistry changes occur and the greater the damage done, emphasizing the importance of early recompression in the treatment of decompression illness.

Very interesting studies have also shown that activation of the complement system may acclimate you to the effects of a decompression accident. This might be a 'using up' process of multiple shallow dives with sub clinical bubbling causing complement activation and having little or none present when a subsequent deeper dive is done. This same process might be the explanation of the excessive fatigue that many divers describe after diving - the fatigue actually being the complement activation damage that is know to occur distant from local bubble sites and the hemoconcentration that occurs.

Individuals who have greater sensitivity to complement activation may be at greater risk for DCS manifestation and more severe DCS injury. Conversely, those with chronically 'used up' complement may be a lesser risk, as in the chronic asthmatic or the atopic patient. . .

The Complement System and Diving

 

[bvanant]

I am interested in the Immune mediated DCS profile hypothesis. I feel like some immune component would play a role, but im not sure to what extent complement would play with bubble formation when Ig levels are low and not fixed to antigen. This is, of course, presuming that Antibodies arent somehow binding/aggregating on microbubbles. However, I feel like this hypothesis could be tested clinically with the use of anti-inflammatory drug administration to patients experiencing DCS symptoms (in conjunction with re compression therapy since it is the gold standard currently). Presumably, if immune mediated reactions were going on, drugs to minimize an immune response should be able to help. However, the unfortunate down side of this would be that an exact mechanism of immune mediation could not be determined as anti-inflammatory drugs tend to have more broadly acting side effects on blood. Nevertheless it would be interesting to see what happens in patients and if potential long term side effects could be reduced.

I mean hell, any hypothesis is worth testing, right?

It's hard for me to imagine how a bubble could lead a dendritic/antigen presenting cell to activate any kind of T-cell or even humoral response let alone how antibodies to bubbles could be targeted. I agree that anti-inflammatory drugs probably have too many off-target effects to be used to probe this idea, but they might help clinically.

Bill

 

[boulderjohn]

.....

Thanks for bringing back the 14 year old study that was discussed earlier and reminding us where the discussion began a couple of years ago.

 

[Bubbletrubble]

It's hard for me to imagine how a bubble could lead a dendritic/antigen presenting cell to activate any kind of T-cell or even humoral response let alone how antibodies to bubbles could be targeted. I agree that anti-inflammatory drugs probably have too many off-target effects to be used to probe this idea, but they might help clinically.

@bvanant: I think you need to open your mind to other related possibilities. You're assuming that the only way to activate the immune system is via bubbles inducing dendritic/APC activation. Modulating the immune system, or any pathway for that matter, doesn't necessarily mean that the entire pathway needs to be turned on. It's possible for a stimulus to act on a molecular intermediary that regulates the pathway at a downstream level. It's also possible for only certain "arms" of the immune system to be activated. Many possibilities exist. You just need to use your imagination.

Several studies demonstrate upregulation of inflammatory molecules in animal models of DCS. Perhaps this inflammatory cascade occurs secondary to ischemia-reperfusion injury. Bigley and Hull wrote a chapter in the text Adhesion Molecules which hypothesizes that cellular adhesion molecules and tissue reperfusion figure into the pathophysiology of DCS. It's a plausible story.

 

[bvanant]

I agree that there are many possibilities here and I wasn't suggesting that dendritic cell/APC activation was the only route but rather that I don't think it plausible as a route. In terms of complement activation, the data that I have seen suggest that while there are changes in complement activation the correlation to DCS events is like 0.15 or so. So I suspect correlation without causality. I am just starting to read about adhesion molecule chemistry/physiology and it will be a while before I can read Bigley and understand it well enough to make sense of it.
The problem with my imagination when it comes to immunology is that the immune system has way more imagination than I do.

Bill

 

[bvanant]

So how does this sound. Nitrogen (or air) bubbles are extremely hydrophobic. It is well known that on very hydrophobic surfaces many physiological proteins can bind and lose their normal structure and expose hydrophobic domains (which are very immunogenic) to the immune system. We will be looking at this in the lab in a few days. This might be particularly important in neonatal ECMO systems (which we make)

Bill